MLDHR (MP31, micropeptide 31; mitochondrial lactate dehydrogenase regulator) is a 31-amino-acid peptide translated from an upstream open reading frame (uORF) in the 5' untranslated region of the PTEN mRNA. It is a distinct product from PTEN and from the in-frame N-terminally extended PTEN-L isoform. The peptide localizes to mitochondria, where it binds lactate dehydrogenases (LDHA and LDHB; binding lost on S5A or Y12A substitution) and limits the mitochondrial conversion of lactate to pyruvate, reported to occur by competing with mitochondrial LDH for NAD+. Loss of the mouse homolog accelerates lactate consumption and production and oxidative phosphorylation, and conditional deletion in astrocytes promotes gliomagenesis, supporting a tumour-suppressive role. The peptide is detected in brain and is reduced or lost in glioblastoma; in glioblastoma cells it also lowers mitochondrial membrane potential and, by competing with the lysosomal V-ATPase for LDHB, causes lysosomal alkalinization and blocks mitophagic flux. All functional data so far come from a single research group.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0005515 protein binding | IPI PMID:33406399 An Upstream Open Reading Frame in Phosphatase and Tensin Hom... | MODIFY | Summary: MP31 interaction with LDHA reported in the primary characterization paper; the interaction is abolished by S5A or Y12A substitutions (UniProt mutagenesis) and underlies inhibition of LDH-mediated lactate-to-pyruvate conversion. Reason: Bare protein binding is uninformative. The functional consequence of the LDHA interaction is inhibition of lactate dehydrogenase activity, which is captured by GO:0160193 L-lactate dehydrogenase inhibitor activity (defined as binding to and reducing LDH activity). The more informative MF should replace this row. Proposed replacements: L-lactate dehydrogenase inhibitor activity Supporting Evidence: PMID:33406399 limits lactate-pyruvate conversion in mitochondria by competing with mitochondrial lactate dehydrogenase (mLDH) for nicotinamide adenine dinucleotide (NAD+) |
| GO:0005515 protein binding | IPI PMID:33406399 An Upstream Open Reading Frame in Phosphatase and Tensin Hom... | MODIFY | Summary: MP31 interaction with LDHB, reported in the primary paper and used again in the follow-up study, where MP31 competes with V-ATPase A1 for LDHB binding. Reason: Bare protein binding is uninformative. The LDHB interaction is the basis of MP31's LDH inhibitor activity (GO:0160193), which is the informative MF; replace with that term. Proposed replacements: L-lactate dehydrogenase inhibitor activity Supporting Evidence: PMID:37280112 We reported that MP31 restricted lactate oxidation in GBM cells by interacting with mitochondrial LDHB. |
| GO:0005739 mitochondrion | IDA PMID:33406399 An Upstream Open Reading Frame in Phosphatase and Tensin Hom... | ACCEPT | Summary: Mitochondrial localization of MP31 shown in the primary paper and restated in the follow-up study from the same group. Reason: Direct experimental localization; mitochondria are where MP31 acts on lactate-pyruvate conversion. Sub-mitochondrial compartment is not stated in the available text, so the general term is appropriate. ORGANELLES check (2026-11-03): the evidence is about the uORF peptide itself (UniProt C0HLV8, curated Mitochondrion from PMID:33406399), not about PTEN or PTEN-L. Rule 2 applies (direct evidence, ACCEPT as the site of the core activity). Stays at the root: the primary paper is abstract-only here, the follow-up (PMID:37280112, full text) uses MitoTracker staining without a sub-mitochondrial assay, and UniProt annotates no transit peptide or transmembrane segment for the 31-residue chain. The N-terminal sequence is arginine-rich and acid-free, which might suggest a presequence, but that is a single uncorroborated line and the side on which mitochondrial LDH acts is itself unsettled, so no sub-compartment row is added. Supporting Evidence: PMID:33406399 limits lactate-pyruvate conversion in mitochondria PMID:37280112 MP31, a phosphatase and tensin homolog (PTEN) uORF-translated and mitochondria-localized micropeptide |
| GO:0005739 mitochondrion | IEA GO_REF:0000044 | ACCEPT | Summary: UniProt subcellular-location keyword mapping (SL-0173 Mitochondrion), derived from the same experimental evidence as the IDA row. Reason: Correct mapping, concordant with the IDA annotation. ORGANELLES check (2026-11-03): UniProt's Mitochondrion location is curated from PMID:33406399 (ECO:0000269) on the peptide's own entry, so the SL-0173 mapping is sound; stays at the root for the reasons given on the IDA row. Supporting Evidence: file:human/MLDHR/MLDHR-uniprot.txt SUBCELLULAR LOCATION: Mitochondrion {ECO:0000269|PubMed:33406399}. PMID:37280112 MP31, a phosphatase and tensin homolog (PTEN) uORF-translated and mitochondria-localized micropeptide |
| GO:0090324 negative regulation of oxidative phosphorylation | IMP PMID:33406399 An Upstream Open Reading Frame in Phosphatase and Tensin Hom... | KEEP AS NON CORE | Summary: Knockout of the mouse MP31 homolog accelerated OXPHOS together with lactate consumption and production. Reason: The loss-of-function phenotype supports the annotation, and the curator had the full text, so it is retained. However, the effect on OXPHOS is downstream of MP31's direct activity, which is to limit mitochondrial lactate-to-pyruvate conversion by inhibiting LDH; reduced pyruvate supply then lowers respiratory flux. MP31 does not act on the respiratory chain or ATP synthase itself, so this is a secondary, indirect process rather than the core one. GO has no term for regulation of lactate oxidation/catabolism that would capture the direct effect more precisely. Supporting Evidence: PMID:33406399 Knocking out the MP31 homolog in mice enhanced global lactate metabolism, manifesting as accelerated oxidative phosphorylation (OXPHOS) and increased lactate consumption and production |
| GO:0160193 L-lactate dehydrogenase inhibitor activity | IDA PMID:33406399 An Upstream Open Reading Frame in Phosphatase and Tensin Hom... | ACCEPT | Summary: MP31 inhibits LDH-mediated lactate-to-pyruvate conversion in mitochondria; it binds LDHA and LDHB, and the abstract describes the mechanism as competition with mitochondrial LDH for NAD+. Reason: This is the core molecular function described in the primary paper and is consistent with the LDH-binding data (binding lost in S5A/Y12A mutants per UniProt) and the GO definition (binds to and reduces LDH activity). The precise mechanism (direct LDH binding versus NAD+ competition) cannot be resolved from the abstract, but the curator had the full text. Evidence comes from a single laboratory and awaits independent replication. Supporting Evidence: PMID:33406399 acting as a "circuit breaker" that limits lactate-pyruvate conversion in mitochondria by competing with mitochondrial lactate dehydrogenase (mLDH) for nicotinamide adenine dinucleotide (NAD+) |
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Download this section (compressed HTML)Q: Does MP31 inhibit LDH by binding the enzyme (as the S5A/Y12A interaction mutants suggest) or by sequestering NAD+ (as the abstract states), and is LDH inhibition reproducible with purified components?
Q: Where in mitochondria do MP31 and its LDH target reside (matrix, intermembrane space, outer membrane), given that the existence of a mitochondrial LDH pool is debated?
Q: Is the endogenous human peptide produced at meaningful levels outside brain, and has any group other than the originating laboratory confirmed its translation and function?
Experiment: In vitro LDH kinetics with synthetic wild-type, S5A and Y12A MP31 peptides, varying NAD+ and lactate, to distinguish enzyme binding from cofactor competition.
Experiment: Sub-mitochondrial fractionation or proximity labelling (e.g. matrix- versus IMS-targeted APEX2) of endogenous MP31 and LDHB.
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